This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain 1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones and corresponding thiones.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimers disease, Parkinsons disease, Huntingtons disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF-receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces anxiolytic-likeeffects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the anxiogenic effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces anxiolytic-like effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g, dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.
The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.
According to another aspect, the present invention provides novel compounds of Formula (1) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formula (1) and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
[1] The present invention comprises novel compounds of Formula (1) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. This invention comprises compounds of Formula (1): 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:
X is O or S;
A=N or CR9;
Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached via an unsaturated carbon atom;
R1 is independently selected at each occurrence from H, C1-C4xe2x80xa0alkyl, C2-C4xe2x80xa0alkenyl, C2-C4xe2x80xa0alkynyl, halo, CN, C1-C4xe2x80xa0haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from:
xe2x80x94H, aryl, heteroaryl and heterocyclyl, or
xe2x80x94C1-C10xe2x80xa0alkyl, C2-C10xe2x80xa0alkenyl, C2-C10xe2x80xa0alkynyl, C3-C8xe2x80xa0cycloalkyl, C5-C8 cycloalkenyl,
C4-C12xe2x80xa0cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, C1-6 alkyloxyC1-6 alkyl, C2-6 alkenyl, C3-6 alkynyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
R3 is selected from:
xe2x80x94H, aryl, heteroaryl and heterocyclyl, or
C1-C4xe2x80xa0lkyl, C3-C6xe2x80xa0alkenyl, C3-C6xe2x80xa0alkynyl, C3-C6xe2x80xa0cycloalkyl, C4-C10 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
R4 is independently selected at each occurrence from: C1-C10xe2x80xa0alkyl, C2-C10xe2x80xa0alkenyl, C2-C10xe2x80xa0alkynyl, C3-C6 cycloalkyl, C4-C12xe2x80xa0cycloalkylalkyl, NO2, halo, CN, C1-C4xe2x80xa0haloalkyl, NR6R7, NR6COR7, NR6CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10xe2x80xa0alkyl, C2-C10xe2x80xa0alkenyl, C2-C10xe2x80xa0alkynyl, C3-C6 cycloalkyl and C4-C12xe2x80xa0cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR6COR7, NR6CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6 and R7 are independently selected at each occurrence from:
xe2x80x94H,
xe2x80x94C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6xe2x80xa0cycloalkyl, C4-C12xe2x80xa0cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0aloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
alternatively, NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from H or C1-C4 alkyl optionally substituted by halogen, C1-C4 alkoxy or C1-C4 halo-alkoxy (1 to 4 halogens);
R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6xe2x80xa0cycloalkyl, C4-C12xe2x80xa0cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94;
R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR15, xe2x80x94COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
n is independently at each occurrence 0, 1 or 2.
[2] Preferred compounds of the above invention also include compounds of Formula (1) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl or pyridyl, each optionally substituted with 1 to 4 R4 substituents.
[3] More preferred compounds of the above invention also include compounds and isomers thereof of formula 1 wherein A is equal to nitrogen (formula 1a), stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof. 
[4] The present invention also relates to compounds, compositions, and stereoisomeric forms, pharmaceutical salts or pro-drugs thereof wherein, in a compound of formula 1, A is equal to CR9 (formula 1b): 
[5] More preferred compounds of the invention include those compounds of formula 1 wherein X is equal to oxygen.
[6] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl or pyridyl and each Ar is optionally substituted with 1 to 3 R4 substituents.
[7] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R2 is:
C1-C10xe2x80xa0alkyl, C2-C10xe2x80xa0alkenyl, C2-C10xe2x80xa0alkynyl, C3-C8xe2x80xa0cycloalkyl, C5-C8 cycloalkenyl, C4-C12xe2x80xa0cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6xe2x80xa0alkyl, C3-C6xe2x80xa0cycloalkyl, halo, C1-C4xe2x80xa0haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl.
[8] More preferred compounds also include those compounds of formula 1 wherein R1, R2 and R3 are independently selected at each position from zC1-6 alkyl.
[9] The present invention comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (1) with the variables as recited above.
The present invention also provides pharmaceutical compositions comprising compounds of Formula (1) with the variables as recited above and a pharmaceutically acceptable carrier.
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix xe2x80x9cnxe2x80x9d means a straight chain alkyl. The prefix xe2x80x9ccxe2x80x9d means a cycloalkyl. The prefix xe2x80x9c(S)xe2x80x9d means the S enantiomer and the prefix xe2x80x9c(R)xe2x80x9d means the R enantiomer. Alkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of Formulae (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
Some compounds of Formula (1) where X=O and A=N, may be prepared from intermediate compounds of Formula (3) using the procedures outlined in Scheme 1. Compounds of Formula (3) may be treated with a halogenating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to give products of Formula (4) (where X is halogen). Halogenating agents include, but are not limited to, Br2, Cl2, I2, N-bromosuccinimide, N-iodosuccinimide or N-chlorosuccinimide. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 150xc2x0 C. The resulting intermediates (4) may then be reacted with alcohols R2OH, where R2 is defined above, in the presence of phosphines Ra3P (where Ra is lower alkyl, phenyl or substituted phenyl or furyl) and an azodicarboxylate ester RbO2CNxe2x95x90NCO2Rb (where Rb is lower alkyl)in an inert solvent at temperatures ranging from xe2x88x9280xc2x0 C. to 150xc2x0 C. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). The choices of phosphine, solvent or azodicarboxylate ester are known to those skilled in the art as described by 0. Mitsunobu (Synthesis, 1 [1981]). Intermediates (5) are treated with a base or an alkali metal in an inert solvent and then reacted with formylating agents YCHO. Y is a halogen, alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxy or cyano group. Bases may include, but are not limited to, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkaline earth metal halides (e.g. methylmagnesium bromide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) and alkali metal bis(trialkylsilyl)-amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C. 
The resulting aldehydes (6) may be converted to acetals (7) by treatment with an acetal-forming reagent in the presence or absence of an acid in an inert solvent. The dotted line between the R groups means that they may or may not be connected. Acetal-forming reagents may be alcohols ROH, where R is lower alkyl, diols HORxe2x80x94ROH where Rxe2x80x94R is lower alkylene, or orthoesters HC(OR)3 where R is lower alkyl. Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Preferred temperatures range from ambient temperature to 150xc2x0 C.
Acetals (7) may then be reacted with a base in an inert solvent, followed by treatment with a compound ArCOY (where Y is a halogen, alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxy or cyano group) to afford intermediates (8). Bases may include, but are not limited to, alkyl lithiums, alkali metal dialkylamides (preferably lithium di-isopropylamide) or alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane or aromatic hydrocarbons (preferably benzene or toluene). Intermediates (8) may then be converted to compounds of Formula (9) by treatment with an acetal-cleaving reagent in an inert solvent. Acetal-cleaving reagents may include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, alkanoic acids, alkylsulfonic acids, substituted phenylsulfonic acids, camphorsulfonic acid or haloalkylsulfonic acids. Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).
The keto-aldehydes (9) may be converted to esters (10) by treatment with an oxidizing agent in an inert solvent to give a carboxylic acid, followed by treatment with an ester-forming reagent. Oxidizing agents include transition metal oxides, such as CrO3 or KMnO4 (with or without a buffering agent such as NaH2PO4), pyridinium dichromate or pyridine-SO3 complex. Inert solvents include water, alkanones (e.g. acetone), aqueous solutions of HCl or H2SO4, or N,N-dialkylformamides. Ester-forming reagents include but are not limited to alcohols RcOH, where Rc is lower alkyl, or orthoesters HC(ORc)3 or combinations of a halogenating reagent and an alcohol RcOH used sequentially or in the same reaction. Halogenating agents include, but are not limited to, POCl3, (COCl)2, SOCl2, N-halosuccinimides, PCl3, PCl5 or PBr3. Inert solvents for the halogenation include, but are not limited to, aromatic hydrocarbons (preferably benzene or toluene), aromatic amines (e.g. pyridine) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0xc2x0 C. to 150xc2x0 C.
Alternatively, aldehydes (9) may be reacted with a compound MCN, where M is H, alkali metal or tetraalkylammonium moiety, in an inert solvent, treated with an oxidizing agent and reacted with alcohols RcOH where Rc is lower alkyl. Oxidizing include, but are not limited to, transition metal oxides, such as CrO3 or MnO2, pyridine-chromium complexes, such as CrO3.C5H5N, pyridinium dichromate or pyridinium chlorochromate or an oxalylchloride-dimethylsulfoxide-triethylamine reagent system, commonly called the Swern oxidation system (D. Swern et al., J. Organic. Chem., 43, 2480-2482 (1978)). Inert solvents of the oxidation include, but are not limited to, halocarbons of 1 to 6 carbons, preferably dichloromethane or 1,2-dichloroethane, lower alkyl alcohols, preferably ethanol or methanol, or lower alkanoic acids, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or combinations thereof.
Esters (10) may then be converted to compounds of Formula (1) where X=O and A=N by one of two methods. Esters (10) may be reacted with hydrazine or its hydrate in an inert solvent, then treated with an alkylating agent in the presence or absence of a base in an inert solvent to provide compounds of Formula (1) where X is O and A=N. Phase transfer catalysts (e.g. tetra-alkylammonium halides or hydroxides) may be optionally employed for the alkylations. Alternatively, esters (10) may be reacted with compounds of Formula R3NHNH2 (where R3 is defined above) in the presence or absence of a base in an inert solvent. Alkylating agents are compounds of the formula R3Z, where Z is halogen, alkanesulfonyloxy (e.g. mesylate), substituted phenylsulfonyloxy (e.g. tosylate) or haloalkanesulfonyloxy (e.g. triflate) groups. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, water, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 100xc2x0 C.
Compounds of Formula (1) where A=N and X=O may be converted to compounds of Formula (1) where A=N and X=S according to the procedures outlined in Scheme 2. Compounds of Formula (1) where A=N, X=O and R3=H may be converted to compounds of Formula (1) where A=N, X=S and R3=H by treatment with a thiocarbonyl-forming reagent in an inert solvent. Thiocarbonyl-forming reagents include but are not limited to, P2S5 or Lawessons reagent. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0xc2x0 C. to 160xc2x0 C. These intermediates may then be converted to compounds of Formula (1) where A=N, X=S and R3 is not equal to H by treatment with an alkylating agent in the presence or absence of a base in an inert solvent. Alkylating agents are compounds of the formula R3Z, where Z is halogen, alkanesulfonyloxy (e.g. mesylate), substituted phenylsulfonyloxy (e.g. tosylate) or haloalkanesulfonyloxy (e.g. triflate) groups. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9280xc2x0 C. to 150xc2x0 C. Alternatively, Compounds of Formula (1) where A=N, X=O and R3 is not equal to H may be converted to compounds of Formula (1) where A=N, X=S and R3 is not equal to H by treatment with a thiocarbonyl-forming reagent in an inert solvent. The reagent and inert solvent are defined above. 
Compounds of Formula (1) where A=CR9 may be prepared from esters (10) by the methods outlined in Scheme 3. Esters (10) may be treated with phosphonium salts of the formula Rd3PCH R9ORf+Xxe2x88x92 where Rd is phenyl or substituted phenyl or phosphonates (ReO)2P(O)CHR9ORf in the presence of a base in an inert solvent to give enol ethers (12). Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether) or cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane). Intermediates (12) may be hydrolyzed to give intermediates (13) in the presence of an acid in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Preferred temperatures range from ambient temperature to 150xc2x0 C. Aldehydes (13) may be treated with amines R3NH2 to generate compounds of Formula (1) where A=CR8 in the presence or absence of an acid or base in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures range from ambient temperature to 150xc2x0 C. 
Alternatively, imidazo[4,5-d]pyridazin-7-ones may be obtained from intermediate (4) as shown in Scheme 4. The intermediate (4) may converted to compound of formula (14) using protecting groups but not limited to benzyl, p-MeO-benzyl or benzyloxymethyl groups. Compound 14 may be converted to compound 20 using the conditions previously described for Scheme 1. Compound 10 may then be deprotected to its NH derivative (21) by standard conditions known in literature. Compound 21 may alkylated under mitsunobu conditions described in Scheme 1 or by alkylation using a base and alkyl halides in the presence of a solvent.